Sunday, December 18, 2016

Leishmania donovani – Evasion of the Host Immune Response

by KH

The human immune system is
extremely complex and has a repertoire of immune cells with many functions. However, the parasite, Leishmania donovani, is still able to evade the immune response of its human host. This parasite utilizes a multitude of mechanisms to disable and evade the host’s immune response.We will focus on the mechanisms L. donovani uses to delay and evade the
phagolysosomal immune response. L. donovani is able to infect phagosomes and evade the degradative properties and harsh environment created in these cells including acidic pH, increased temperatures, and increased oxidative and nitrosative stress1. We will first start with background information about L. donovani and the life cycle
of this parasite before examining how it evades the host immune system.

Leishmaniasis is a vector-borne disease caused by the unicellular, eukaryotic, obligate intracellular organism Leishmania donovani. ‘Obligate intracellular organism’ is just a fancy way to say that it is a parasite. It means that parasites are unable to survive the conditions outside of their host because they typically rely on the cellular machinery of the host or
the stable environment provided by the host. The species that cause human infection can exist in three forms. The first is the more common cutaneous leishmaniasis form which causes skin sores2. The second main form is the visceral
leishmaniasis form which infects internal organs such as the spleen, bone marrow, and liver3. The third
form is usually less common and is known as the mucosal leishmaniasis form. This type is typically a
consequence of species of the cutaneous form spreading past the skin into the mucosal
membranes of the nose, throat, and mouth2.

The life cycle of Leishmania donovani involves alternating between two hosts, the female phlebotomine sandfly and a human3,4 (Fig. 1). Although there is no official starting point for the life cycle of this organism, we will start at the point at which L. donovani enters a human host. A female sandfly infected with L. donovani will bite a human to take a blood meal while simultaneously injecting L. donovani, in its promastigote stage, into the human. The promastigote cell is the mammalian-infective form of the parasite and is a thin elongated cell5. These cells have a flagellum which is a filament protruding from the cell that allows the parasites to move and swim around. Once these cells are injected into the human host, they swim around until they are engulfed by phagosomes in
a process called phagocytosis. Phagosomes are a type of immune system cell whose function is to ingest foreign organisms and degrade them. Inside the phagosome, the promastigotes lose their flagella and ability to swim around. They transform from the
promastigote cells into amastigote cells. Amastigotes are small spherical cells without a flagellum5. At this stage of the life cycle, amastigotes grow and divide in the phagosomes until the phagosome becomes too full and bursts,
allowing the amastigote cells to infect more phagosomes2. It is at this stage in the life cycle that it is determined if the human will show symptoms of infection or whether the cutaneous or visceral leishmaniasis form will develop. The form the parasite takes on usually depends on the species of L. donovani and the health of the host3. Female phleobtomine sandflies can become infected by taking a blood meal from a human infected with L. donovani. In the infected female sandflies, the phagosomes containing the amastigote cells are digested in the gut of the sandfly, releasing the amastigotes. In the midgut of the sandfly, the amastigotes transform back into the promastigote stage where they re-develop their flagella and are able to move through the midgut epithelial wall to enter the salivary glands. In the salivary glands of the sandfly, the parasites will be injected into the human host the next time the female sandfly takes a blood meal to
continue the cycle2.

Figure 1. Life cycle
of Leishmania donovani in both the
sandfly and human hosts3.

Phagosome maturation is the process by which a phagosome containing foreign material fuses with a lysosome during phagocytosis to create a phagolysosome. It is a critical step in the killing and degradation of the ingested foreign organism6. Lysosomes are membrane-bound compartments containing degradative enzymes that break down the ingested material taken up by the phagosome in the mature phagolysosome.

To survive the harsh conditions in the phagosome described above, the promastigotes engulfed by the phagosome briefly prevent the maturation of the phagolysosome by expressing lipophosphoglycan (LPG) which is a sugar-phosphate molecule that is attached to the surface of the promastigotes7. This cell surface molecule can inhibit a variety of signaling, metabolic,
and immune response molecules. It can also induce the accumulation of a structural molecule that surrounds the phagolysosome7. This structural component is called actin and is a single structural molecule that can link up to other actin to form large chains. The interaction between the parasite and the phagosome surface receptors, which activates the single actin molecules to assemble and surround the foreign organism, allow for the parasite to be engulfed7. The phagosome has a layer of actin surrounding itself that helps with engulfment of foreign organisms that slowly disappears as the phagosome goes through maturation. To be able to fully mature via fusion of the phagosome and lysosome, all of the actin needs to disappear for the fusion to occur7. If LPG prevents the actin from fully disappearing for a transient amount of time to allow the fusion to occur, it is able to delay the full maturation of the phagolysosome. This delay of the fusion of the phagosome and lysosome can be seen by the delay or no expression of late maturation markers normally found on the mature phagolysosome6. This evidence suggests that some of the surface molecules on these parasites can briefly inhibit phagosome and lysosome fusion which allows just enough time for the promastigotes to transform into the amastigotes that are capable of withstanding the degradative enzymes and acidic pH introduced by the lysosome in the mature phagolysosome6.

During its life cycle, Leishmania donovani is able to evade the host immune response and persist. More specifically, these parasites can survive in immune system cells known as phagolysosomes in the host, eventually killing them by bursting
through the membrane to be released to infect more phagosomes. The parasites are capable of doing this because the mammalian-infective promastigotes quickly transform into amastigotes after they are engulfed by phagosomes. The amastigotes are
resistant to the degradative properties of mature phagolysosomes which allows the parasite to persist and evade the immune response. With all of this taken together, Leishmania donovani can be an interesting pathogen for studying and understanding mechanisms of host immune
system evasion.

Gossage SM, et al. 2003. Two
Separate Growth Phases during the Development of Leishmania in Sand
Flies: Implications for Understanding the Life Cycle. International
Journal for Parasitology, 33(10):1027-1034.

Pulvertaft, RJ, Hoyle, GF.
1960. "Stages in the Life-cycle of Leishmania donovani".
Transactions of the Royal Society of Tropical Medicine and Hygiene. 54(2):191–6.

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